Li Zeyang, Ngu Rachael, Naik Aditya Anil, Trinh Kaitlyn, Paharkova Vladislava, Liao Hanyue, Liu Yulu, Zhuang Cindy, Le Danh, Pei Hua, Asante Isaac, Mittelman Steven D, Louie Stan
Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA.
Division of Pediatric Endocrinology, University of California Los Angeles (UCLA) Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, California, USA.
Eur J Clin Invest. 2024 Dec;54(12):e14307. doi: 10.1111/eci.14307. Epub 2024 Sep 10.
Acute lymphoblastic leukaemia (ALL) is the most common type of childhood leukaemia with effective chemotherapeutic treatment. However, obesity has been associated with higher ALL chemoresistance rates and lower event-free survival rates. The molecular mechanism of how obesity promotes chemotherapy resistance is not well delineated.
This study evaluated the effect of adipocyte maturation on sequestration and metabolism of chemotherapeutic drug daunorubicin (DNR).
Using targeted LC-MS/MS multi-analyte assay, DNR sequestration and metabolism were studied in human preadipocyte and adipocyte cell lines, where expressions of DNR-metabolizing enzymes aldo-keto reductases (AKR) and carbonyl reductases (CBR) were also evaluated. In addition, to identify the most DNR-metabolizing AKR/CBR isoforms, recombinant human AKR and CBR enzymes were subject to DNR metabolism. The results were further validated by AKR-, CBR-specific inhibitors.
This report shows that adipocyte maturation upregulates expressions of AKR and CBR enzymes (by 4- to 60- folds, p < .05), which is positively associated with enhanced sequestration and metabolism of DNR in adipocytes compared to preadipocytes (by ~30%, p < .05). In particular, adipocyte maturation upregulates AKR1C3 and CBR1, which are the predominate metabolic enzyme isoforms responsible for DNR biotransformation to its metabolites.
Fat is an expandable tissue that can sequester and detoxify DNR when stimulated by obesity, likely through the upregulation of DNR-metabolizing enzymes AKR1C3 and CBR1. Our data partially explains why obese ALL patients may be more likely to become chemoresistant towards DNR, and provides evidence for potential clinical investigation targeting obesity to reduce DNR chemoresistance.
急性淋巴细胞白血病（ALL）是儿童白血病中最常见的类型，有有效的化疗方法。然而，肥胖与ALL更高的化疗耐药率和更低的无事件生存率相关。肥胖促进化疗耐药的分子机制尚未完全阐明。
本研究评估脂肪细胞成熟对化疗药物柔红霉素（DNR）的隔离和代谢的影响。
使用靶向液相色谱-串联质谱多分析物测定法，在人前脂肪细胞和脂肪细胞系中研究DNR的隔离和代谢，同时评估DNR代谢酶醛糖还原酶（AKR）和羰基还原酶（CBR）的表达。此外，为了鉴定最主要的DNR代谢AKR/CBR同工型，将重组人AKR和CBR酶进行DNR代谢实验。结果通过AKR、CBR特异性抑制剂进一步验证。
本报告显示，脂肪细胞成熟上调AKR和CBR酶的表达（上调4至60倍，p < 0.05），与前脂肪细胞相比，这与脂肪细胞中DNR的隔离和代谢增强呈正相关（增加约30%，p < 0.05）。特别是，脂肪细胞成熟上调AKR1C3和CBR1，它们是负责将DNR生物转化为其代谢物的主要代谢酶同工型。
脂肪是一种可扩张的组织，在肥胖刺激下可隔离并使DNR解毒，可能是通过上调DNR代谢酶AKR1C3和CBR1实现的。我们的数据部分解释了为什么肥胖的ALL患者可能更易对DNR产生化疗耐药，并为针对肥胖以降低DNR化疗耐药性的潜在临床研究提供了证据。
